Resolution of ketoprofen

Abstract

A method for resolving (±)-(α)-(3-benzoylphenyl) propionic acid is disclosed. The method comprises: i) converting said propionic acid with (-)-cinchonidine in a solvent comprising a mixture of an aliphatic ester and an alkyl alcohol; ii) separating teh diastereomeric salt from such conversion; iii) purifying said separated diastereomeric salt by a single recrystallization; and iv) isolating highly pure (+)-α-(3-benzoylphenyl) propionic acid without any further recrystallization.

We claim: 
     
       1. A method for resolving (±)-(α)-(3-benzoylphenyl)-propionic acid comprising: (i) converting said propionic acid with (-)-cinchonidine in a solvent comprising a mixture of an aliphatic ester and an alkyl alcohol, said aliphatic ester being from about 2 to about 20 times in excess of said alkyl alcohol;   (ii) separating the diastereomeric salt from such conversion;   (iii) purifying said separated diastereomeric salt by a single recrystallization; and   (iv) isolating highly pure (+)-(α)-(3-benzoylphenyl)-propionic acid without any further recrystallization.   
     
     
       2. The method according to claim 1 wherein said aliphatic ester is ethyl acetate. 
     
     
       3. The method according to claim 1 wherein said alkyl alcohol is selected from the group consisting of methyl alcohol, ethyl alcohol, n-propyl alcohol and i-propyl alcohol. 
     
     
       4. The method according to claim 3 wherein said alcohol is methyl alcohol. 
     
     
       5. A method for resolving (±)-(α)-(3-benzoylphenyl)-propionic acid comprising: (i) converting said propionic acid with (-)-cinchonidine in a solvent at 30°-70° C., comprising a mixture of an aliphatic ester and an alkyl alcohol, said aliphatic ester being from about 2 to about 20 times in excess of said alkyl alcohol;   (ii) separating the diastereomeric salt from such conversion;   (iii) purifying said separated diastereomeric salt by a single recrystallization; and   (iv) isolating highly pure (+)-(α)-(3-benzoylphenyl)-propionic acid without any further recrystallization.   
     
     
       6. The method according to claim 5 wherein said aliphatic ester is ethyl acetate. 
     
     
       7. The method according to claim 5 wherein said alkyl alcohol is selected from the group consisting of methyl alcohol, ethyl alcohol, n-propyl alcohol and i-propyl alcohol. 
     
     
       8. The method according to claim 7 wherein said alcohol is methyl alcohol. 
     
     
       9. A method for resolving (+)-(α)-)3-benzoylphenyl)-propionic acid comprising: (i) converting said propionic acid with (-)-cinchonidine by admixing said propionic acid and said cinchonidine with an aliphatic ester solvent;   (ii) adding to said admixture an alkyl alcohol, said aliphatic ester being about 2 to about 20 times in excess of said alkyl alcohol;   (iii) repeating a diastereomeric salt from said admixture of step ii,   (iv) purifying said separated diastereomeric salt by a single recrystallization; and   (v) isolating highly pure (±)-(α)-(3-benzoylphenyl)-propionic acid without any further recrystallization.   
     
     
       10. The method according to claim 9 wherein said aliphatic ester is ethyl acetate. 
     
     
       11. The method according to claim 9 wherein said alkyl alcohol is selected from the group consisting of methyl alcohol, ethyl alcohol, n-propyl alcohol and i-propyl alcohol. 
     
     
       12. A method for resolving (+)-(α)-(3-benzoylphenyl)-propionic acid comprising: i. converting said propionic acid with (-)-cinchonidine by admixing said propionic acid and said cinchonidine with an aliphatic ester solvent at 30°-70° C;   ii. adding to said admixture an alkyl alcohol, said aliphatic ester being about 2 to about 20 times in excess of said alkyl alcohol;   iii. repeating a diastereomeric salt from said admixture of step ii;   iv. purifying said separated diastereomeric salt by a single recrystallization; and   v. isolating highly pure (±)-(α)-(3-benzoylphenyl)-propionic acid without any further recrystallization.   
     
     
       13. The method according to claim 12 wherein said aliphatic ester is ethyl acetate. 
     
     
       14. The method according to claim 12 wherein said alkyl alcohol is selected from the group consisting of methyl alcohol, ethyl alcohol, n-propyl alcohol and i-propyl alcohol.